The following projects have been or are currently being conducted by CATE. 1) Modulation of central glutamate by acamprosate A prevalent theory states that progressive emergence of a hyperglutamatergic state is key to the pathophysiology of alcoholism, and is associated both with emotional dysregulation (leading to craving and relapse), and neurotoxicity (leading to loss of grey matter and cognitive impairment). Acamprosate is a medication thought to target the hyperglutamatergic state. Here we used magnetic resonance spectroscopy (MRS) as a translational biomarker to obtain a measure of central glutamate using single-voxel 1H-MRS at 3T in the anterior cingulate cortex. The primary results of this study have been published in Archives of General Psychiatry, 2010. We are currently performing secondary analyses on biospecimens to assess the effects of treatment on cytokine levels in the CSF and plasma. 2) Effect of naltrexone on craving and ethanol-induced brain activity Findings from animal and human studies indicate that the rewarding properties of ethanol arise in part from a complex interaction between alcohol, endogenous opioids, and dopamine systems. Naltrexone (NTX), an opioid receptor antagonist, has been studied widely in both preclinical and clinical research for the treatment of alcoholism. Numerous clinical studies have shown that short-term use of NTX in alcohol-dependent patients effectively prevents relapse and reduces the level of craving. This protocol is the first study which involves administering IV alcohol to treatment-seeking alcohol dependent patients. Following detoxification, patients are randomized, using a double-blind design, to receive NTX or placebo throughout the course of their hospitalization. This study examines interactions between brain alcohol exposure and naltrexone treatment on the processing of positive and negative emotional stimuli using fMRI. Subject accrual is complete. Data analysis reveals that at a BAL of approximately 0.8 g% there is a lack of ethanol-induced BOLD response in the ventral striatum (VS). This result is in contrast to our previous findings in social drinkers that showed activation of the VS. These findings suggest that alcoholics in the later stages of the addictive process may develop a degree of tolerance to the rewarding properties of alcohol. 3) NK1R antagonism in alcoholism co-morbid with PTSD Alcoholism is the most common co-morbidity in men with PTSD and the second most common in women with this disorder. It is theorized that stress associated with PTSD (e.g., fear/anxiety, anger, hyper vigilance) promotes negatively reinforced use of alcohol to cope with negative affect. Therefore, we hypothesized that Substance P (SP)/NK1R signaling may be an attractive target for treatment of co-morbid alcoholism and PTSD. We asked whether NK1R blockade would suppress alcohol craving induced by stress or alcohol-associated stimuli, and whether it will improve PTSD symptoms in patients with co-morbid alcoholism and PTSD. Patient accrual for this protocol is complete; data analysis is ongoing. 4) Corticotropin-releasing hormone receptor 1 (CRH1) antagonism and stress-induced craving in alcohol dependent women with high anxiety As alcoholism evolves, a shift occurs from positively to negatively reinforced alcohol use. Along the way, stress becomes a major trigger of relapse and excessive alcohol intake. Corticotrophin-releasing hormone (CRH) plays a major role in this state. We have negotiated a CRADA with GlaxoSmithKline, obtained an IND, and initiated a protocol that uses GSK561679 (CRH antagonist) as a translational tool in anxious female alcoholics (preclinical toxicology studies show that its use leads to a suppression of spermatogenesis, thus precluding its use in males). The hypothesis is that GSK561679 will reduce alcohol craving in response to the combined challenges of the Trier Social Stress Task, alcohol-cue exposure, and guided imagery scripts. We will also examine whether GSK561679 will reduce spontaneous craving, reduce fMRI BOLD responses to negative affective stimuli within the ventral visual stream, medial temporal lobe and/or the anterior insula, and modulate blood markers of endocrine function in a manner indicative of anti-stress effects. Twenty-four subjects have been enrolled, 17 have completed. 5) CRH1 antagonism in anxious alcoholics This study uses another CRH1 antagonist, pexacerfont, obtained through a CRADA with Bristol Meyers Squibb. Pexacerfont is also an orally available, brain penetrant selective CRH1 antagonist. It has the advantage that safety has been established for the administration in both males and females. Because of the broader utility of pexacerfont in a therapeutic area where the majority of patients are male, we chose pexacerfont as the tool for a consortium of NIAAA/NIDA investigators who will use it in a cluster of related protocols. In the pexacerfont alcohol protocol, we will examine whether the CRH1 antagonist will reduce alcohol craving in response to the challenges as previously described for the GSK561679 CRH antagonist. We will also examine whether pexacerfont will reduce fMRI BOLD responses to a novel social stress challenge developed jointly with our NIDA collaborators. Forty-four subjects have been enrolled, 37 have completed. 6) Collaborative project with NIMH: Imaging cannabinoid CB1 receptors in patients with alcohol dependence The brain endocannabinoid (EC) system involves endogenous cannabinoid agents (ECs) that act upon specific receptors (CB1 and CB2). ECs and CB1 receptors appear to modulate the brain reward system. During chronic alcohol exposure, EC levels in the brain are elevated and CB1 receptor levels are consequently reduced; this appears to be reversible following withdrawal. To what extent ECs and CB1 receptors are involved in the pathophysiology of alcohol dependence in humans is currently unknown. In this protocol, we utilize positron emission tomography to explore CB1 receptor abnormalities at various stages of alcohol withdrawal in humans. Results show that alcohol dependence is associated with a widespread reduction of cannabinoid CB1 receptor binding in the human brain, and this reduction persists at least 2-4 weeks into abstinence. The correlation of reduced binding with years of alcohol abuse suggests an involvement of CB1 receptors in alcohol dependence. The results are published in Molecular Psychiatry (2012). 7) Pilot study of deep brain stimulation (DBS) for the treatment of alcoholism Case reports of beneficial effects from DBS of the ventral striatum in alcoholism have been published, but no controlled data are available. In collaboration with NINDS and Medtronic, a DBS protocol that uses a controlled design has been approved by the IRB, and is under review by the FDA. The review process of this protocol has been extensive. Patient accrual will commence in the fall of 2012. 8) Role of proinflammatory signaling in alcohol craving Ethanol-induced activation of innate immunity has emerged as a potential mechanism for understanding the pathophysiology of alcoholism. The objective of the present study is to evaluate the role of proinflammatory signaling in alcohol craving. The peroxisome proliferator-activator receptor gamma agonist pioglitazone, which modulates glial activity, will be used as an experimental treatment. Guided imagery scripts will be used as an established set of stimuli to induce craving. Low dose lipopolysaccharide (LPS) administration, which activates proinflammatory signaling, will be used as a novel challenge and evaluated for its ability to provoke alcohol craving. If LPS in fact induces alcohol craving, the present design will allow evaluation of whether pioglitazone can inhibit this response. One patient has been enrolled.